Benznidazole solid dispersions: a new strategy to improve treatment of Trypanosoma cruzi infection

ALICIA CID; OLGA SÁNCHEZ NEGRETTE; LUIS ANTONIO PARADA; PAULA GABRIELA RAGONE; FEDERICO RAMOS; JOSÉ MARÍA BERMUDEZ; CAROLINA DAVIES; MARÍA CELIA MORA; ANALÍA SIMONAZZI

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Protozoología

Benznidazol (BZL) and Nifurtimox are the only drugs approved to specifically treat T. cruzi infection. Both are orally administered, and can present adverse side effects or treatment failure. BZL, the first-line treatment in Argentina, is a compound with low solubility in water, limited bioavailability, and is administered for long periods of time at high doses. One possibility to improve treatment lies on pharmaceutical formulations designed to increase water solubility of poorly soluble molecules. For that reason, a new liquid formulation based on an amphiphilic polymer (P) acting as a carrier of BZL was tested on mice models of acute and chronic T. cruzi infection. Female Swiss mice (N=57) were infected with Tulahuén strain (300 parasites/mouse for the acute phase model, and 50 parasites/mice for the chronic phase model). Treatments were given orally once a day, every day for 2 months, starting at 5 days post-infection (dpi) in the acute phase model, and 150 dpi in the chronic phase. Doses of BZL-P were: 15 mg/Kg/day, 60 mg/Kg/day, and 60 mg/Kg/day twice per week. Controls: placebo, and the commercial formulation BZL-C at 50 mg/Kg/day. Results showed that the effect of BZL was dose-dependent: higher doses (60 and 50 mg/Kg/day) were more effective in clearing parasites from blood and tissue than lower doses (15 mg/Kg/day). Intermittent administration of BZL (twice a week) was effective in reducing parasitaemia in blood, but it did not prevent the establishment of parasites in muscle or heart tissue. The new formulation was as effective as BZL-C at equivalent doses. Adverse effects were not detected. Being liquid, the new formulation tested in these experiments may provide an alternative for better dosing, since commercial tablets must be divided, mashed and weighted to achieve a given dose. A liquid formulation of BZL could represent an improvement for treatment in children and adults.